DOUG MELTON RELEASES NEW STEM CELL LINES

by
Charlie Schmidt

April 2nd, 2004

Doug Melton( photo by Rick Friedman)

MCB Professor Doug Melton has produced 17 new human embryonic stem cell lines and made them available to scientists around the world. The cells were created with private money, a move that allowed Melton and his colleagues to bypass White House limits on this type of research. These actions illuminate the rise in private funding for stem cell research and draw renewed attention to the issue as a political tinderbox. The new cells are described in the March 25 issue of the New England Journal of Medicine.

Under the right physiologic or experimental conditions, embryonic stem cells will form adult cells of any type. Melton has doubled the number of embryonic cells available to study conditions ranging from heart disease to Alzheimer's. But the new cells come with a hitch: Anyone using them for research must forgo federal funding. According to White House restrictions, use of federal funds is limited solely to studies with approved embryonic cells lines registered by the National Institutes of Health (NIH). Fifteen such lines are currently in existence - the remnants of 60 set aside in August 2001 by President Bush. The federal limits are based on the administration's view that the embryos from which stem cells are derived are alive, and that cell extraction terminates that life. Many scientists do not agree with this belief. Melton's embryos were obtained from Boston IVF, a local in-vitro fertilization clinic that would have otherwise discarded them.

Two Years in the Making

Melton's plan to develop the cells was hatched two years ago, while he was researching insulin-dependent, or juvenile diabetes. This condition afflicts his two children, who require frequent injections of insulin to stay alive. Melton hoped to use embryonic cells to make insulin-secreting beta cells of the pancreas, thus advancing new treatments for this disease, which affects millions of people. But his efforts to obtain viable cells from the NIH registry were thwarted by roadblocks and red tape: The cells took months to arrive, they were expensive, and they didn't grow well in the laboratory. Similar problems are often reported by other scientists - indeed many complain that federally approved cell lines are not only too few but also poor in quality.

Joking that he is impatient by nature, Melton decided to take matters into his own hands. "The appropriate cell lines just weren't available to us," he says. "So, I gave up and focused on creating my own."

Melton obtained funding from Harvard, the Juvenile Diabetes Research Foundation, and the Howard Hughes Medical Foundation; and armed himself with informed consent from a Harvard institutional review board. He then coordinated with Boston-IVF of Waltham, MA to obtain embryos for stem cell extraction. Several hundred frozen embryos were donated by the clinic. Melton worked with Chad Cowan and Andrew McMahon from Harvard, and Doug Powers from Boston IVF, to painstakingly isolate the stem cells from the embryonic material.

The entire process required some deft logistical maneuvering. All the laboratory equipment had to be segregated from that used for publicly funded research. Stem cell cultivation took place in a dedicated laboratory; and associated tools were stored in boxes labeled with a red sticker. Melton recalls the process as awkward, but surmountable. "It was like making four dishes for dinner and making one of these with its own salt, pepper, and other ingredients," he explains.

The 17 lines that were ultimately established comprise the fruits of this effort. Looking forward, Melton says, "I have one research priority with these cells. I am fully focused on turning them into pancreatic beta cells. But I'm hopeful that they will also be used by others to make neurons, or cardiac muscle cells, or other cells."

The act of creating specialized cell types from stem cell reagents is a difficult challenge. The goal is to advance a futuristic medical paradigm called "cell therapy," whereby patients are given actual cells, rather than drugs, to repair damaged or diseased tissues. A great deal of effort is needed to advance this aim. The process of stem cell differentiation is complex and dependent on mysterious biochemical pathways that scientists must first understand, and then harness, to achieve clinical goals. Melton says he will focus first on the genetic signals that stimulate pancreatic beta-cell formation; using various techniques to identify how genes are turned on and off during the process. The research will be guided in part by findings in animal models, including mice, frogs, and zebrafish, he says.

But while Melton's stem cells are valuable for research, they are not appropriate for clinical trials in people. Like all other available embryonic stem cell lines, Melton's cells were cultured on mouse-derived feeder layers of embryonic tissue that provide nutrients for growth. Because the layers could contain animal viruses, they are not "clinically compliant," nor do they address the ongoing challenge of isolating stem cells without animal products. Melton says he isn't preoccupied with the need for human feeder layers, which are required to make therapeutic stem cells. "That's not our concern right now," he says. "Our goal is make pancreatic beta cells. I wish the mouse-to-human feeder layer was my only problem, that's going to be easy to solve."

In the meantime, Melton touts his cells as optimal research tools: They're easy to grow, they're well characterized (meaning they exhibit fundamental properties of stem cells, i.e. the capacity to proliferate in culture without differentiating into a particular cell type) and they have a low "passage number," meaning that haven't been excessively replicated.

Shipping in Uncertain Times

The new cells were first announced on the NEJM's website on March 3, weeks ahead of the print release date, so scientists could immediately request the cells, which Melton will provide for free. Several hundred vials of stem cells have been frozen and prepared for shipping. Melton expects the current stocks will supply qualified recipients for six months or more, but he concedes the true demand is hard to gauge. "These cells can't be studied with federal funds, so that could significantly reduce the number of investigators who can use them," he says.

Melton's stem cells arrive on the heels of a growing debate over the federal government's role in this research. Democratic presidential candidate John Kerry has chided the Bush administration for being "anti-science" in its approach to stem cells. State governments and universities including Stanford, Johns Hopkins, Wisconsin-Madison, Minnesota, U.C.L.A. are raising money designed to limit reliance on federal funds for stem cells. Speaking for the White House, presidential spokesperson Trent Duffy was quoted in the March 4 issue of the Wall Street Journal as saying "We should not cross a fundamental moral line by funding or encouraging the destruction of human embryos."

But Melton points out that 200,000 to 400,000 fertilized eggs in the United States are already slated for destruction. "We used a tiny portion of these for our own efforts," he says. "From that point of view, one could almost consider our position pro-life. We took something that was going to be destroyed and isolated cells from it that could improve the lives of people suffering from disease and trauma. I don't know of any scientist who thinks this was a bad idea or that it should not have been done."

A New Stem Cell Research Center

On April 23, 2004 Melton will be among those presiding over a new Harvard-based center established to grow and study human stem cells. Tentatively called the Harvard Stem Cell Institute, the center will bring together researchers from the university and its affiliated hospitals. Embryonic cells grown at the center will be carefully sequestered so as to not conflict with federal policy. Advances in the field, should they prove fruitful, may eventually provoke a face-off between scientists and an administration that is largely opposed to experiments with early-life stage human embryos. But according to Melton, new embryonic cell lines will be needed to meet scientific demands. "The number needed is far greater than that which is available," he says. "We need stem cells that represent the full genetic diversity of the population, in particular with respect to diseases like Alzheimer's and diabetes. Developing embryonic stem cells that have these defects represent the best way I know of to get to the root causes of these diseases. I'll be sorry if this is the end of our efforts. My hope is that this is just the beginning."